Using biothesiometer, Neuropathy Symptom Score, and Neuropathy Disability Score for the early detection of peripheral neuropathy: A cross-sectional study

Patients with peripheral neuropathy could have damaged peripheral nerves, which leads to sensory and motor dysfunction. Diabetes, infections, and trauma are the major causes of peripheral neuropathy. Vibratory perception threshold (VPT) tools are commonly used to detect peripheral neuropathy. This study aims to determine the assessment of peripheral neuropathy through the different diagnostic tools in the community in Malaysia. A total number of 1283 participants were recruited from the seven retail pharmacies located in Selangor, Malaysia. The peripheral neuropathy test was conducted based on VPT tools on both feet using the digital biothesiometer. Following that, Neurological Symptom Score (NSS) and Neurological Disability Score (NDS) were taken from the participants to assess the neurological symptoms. Participants had an average age of 40.6 ± 12.9 years and were mostly of Chinese ethnicity (54.1%). The findings show that increasing age was associated with more severe peripheral neuropathy across the various assessment tools, but gender differences were found with the biothesiometer test and ethnicity has severity in the biothesiometer and disability scores. The sensitivity and specificity of the biothesiometer test were 0.63 and 0.84, respectively. The combined tool NSS and NDS had high specificity and a high positive predictive value, suggesting that it could be a reliable indicator of peripheral neuropathy when both scores are elevated. The findings show that the biothesiometer test, NSS, and NDS are considered screening VPT tools for diagnosing peripheral neuropathy. However, further evaluation and diagnostic testing are necessary in cases of a positive test result.

Patients with peripheral neuropathy could have damaged peripheral nerves, which leads to sensory and motor dysfunction.Diabetes, infections, and trauma are the major causes of peripheral neuropathy.Vibratory perception threshold (VPT) tools are commonly used to detect peripheral neuropathy.This study aims to determine the assessment of peripheral neuropathy through the different diagnostic tools in the community in Malaysia.A total number of 1283 participants were recruited from the seven retail pharmacies located in Selangor, Malaysia.The peripheral neuropathy test was conducted based on VPT tools on both feet using the digital biothesiometer.Following that, Neurological Symptom Score (NSS) and Neurological Disability Score (NDS) were taken from the participants to assess the neurological symptoms.Participants had an average age of 40.6 ± 12.9 years and were mostly of Chinese ethnicity (54.1%).The findings show that increasing age was associated with more severe peripheral neuropathy across the various assessment tools, but gender differences were found with the biothesiometer test and ethnicity has severity in the biothesiometer and disability scores.The sensitivity and specificity of the biothesiometer test were 0.63 and 0.84, respectively.The combined tool NSS and NDS had high specificity and a high positive predictive value, suggesting that it could be a reliable indicator of peripheral neuropathy when both scores are elevated.The findings show that the biothesiometer test, NSS, and NDS are tool that assesses the presence and severity of neuropathic symptoms. 10The NDS is a commonly used clinical examination method that assesses neuropathy signs. 4 study reported that 35% of patients with type 2 diabetes had peripheral neuropathy diagnosed with NSS and NDS. 11A study among patients with type 2 diabetes mellitus attending a follow-up visit in an outpatient clinic at Universiti Kebangsaan Malaysia Medical Center found that the prevalence of DPN was 79.1%. 12Another study in the Primary Care Clinic, Universiti Hospital, which included 138 diabetic patients assessed using the NSS and NDS, reported that the prevalence of DPN was high at 50.7% 13 and another study conducted among the Malaysian population reported 54.1% of DPN based on nerve conduction study. 11][9] The objectives of this study were as follows: to determine the sensitivity, specificity, PPV, and NPV of the biothesiometer test, NSS questionnaire, and NDS questionnaire for detecting peripheral neuropathy compared with the reference standard of clinical examination findings; to evaluate if the combined use of the NSS and NDS questionnaires with a threshold score >10 provides higher accuracy in diagnosing peripheral neuropathy compared with the individual scores; and to assess the association of age, gender, and ethnicity on peripheral neuropathy severity across the various screening modalities.

INTRODUCTION
Peripheral neuropathy is a condition that affects the peripheral nervous system and can present with a range of symptoms, some of which may be vague.][3][4] Symptoms associated with diabetic peripheral neuropathy (DPN) may differ based on the specific nerves that are affected.Numbness, prickling, or tingling in the hands or feet may develop gradually as a result of sensory nerves receiving information from the skin, including temperature, pain, vibration, and contact.6][7][8][9] The diagnosis of DPN, along with the assessment of its worldwide prevalence and incidence rates, continues to pose challenges.Diverse viewpoints exist regarding the efficacy of expanding screening efforts to facilitate early diagnosis and the initiation of treatment prior to the onset and progression of the condition.8][9] However, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of these tools have not been consistently reported in the literature.A study's findings have shown that vibratory perception threshold (VPT) measured with biothesiometer exhibits favorable diagnostic accuracy in detecting DPN when compared with clinician diagnosis, neuropathy symptom scores, and abnormal nerve conduction. 5The Michigan Neuropathy Screening Instrument (MNSI) is a composite measure of vibration perception with a 128-Hz tuning fork, thermal perception with a metallic rod, pin-prick sensation, and Achilles tendon reflexes. 3The NSS is a simple and reliable Using biothesiometer, Neuropathy Symptom Score, and Neuropathy Disability Score for the early detection were that the participants must be Malaysian, aged ≥18 years, and willing to sign the informed consent form.Those critically ill and/or mentally challenged were not eligible to participate in this study.Participants were recruited using a convenient sampling method.

Sample size calculation
Using the StatCalc feature in Epi Info 7.0, the sample size was determined by the prevalence of peripheral neuropathy, which was 2.38% among the Parsi community in Bombay. 14The sample size required was 899 with a 95% confidence interval (CI), power of 80%, and a p-value of <0.05.However, to account for potential incomplete or missing data at a rate of 30%, the total number of participants needed was adjusted to 1283.

Data collection tools
The questionnaire is self-administered and clarified with the researchers.The questionnaire has been divided into four sections, each serving a unique purpose.In the initial section, we sought to collect comprehensive socio-demographic information such as age, gender, ethnicity, and personal monthly income in Ringgit Malaysia.In addition, this section probed participants about their lifestyle factors, including alcohol consumption, smoking habits, and dietary preferences (vegetarianism).Co-morbidities were explored in this section, with inquiries regarding the presence of conditions such as hypertension, diabetes, neurological disorders, and any family history of neurological disorders.Subsequent sections of the questionnaire were dedicated to the evaluation of peripheral neuropathy through screening tests, as well as the assessment of neuropathy symptom scores and neuropathy disability scores.

Biothesiometer test
The peripheral neuropathy test was the determination of the VPT on both feet using the digital biothesiometer by P&G (Diabetik Foot Care Model: Vibrometer-VPT model 1; The Digital 0-50 V indicator with a portable Vibration probe functioning at 230 V, ±20%, AC, 50-Hz Mains operation).The biothesiometer probe can vibrate with an amplitude proportional to the square of the applied voltage.To test the vibration perception threshold, a vibration probe must be placed on six sites on each foot.The sites are the plantar aspects of the tip of the first toe, the base of the first, third, and fifth toes, the medial aspect of the midfoot and at the heel.After patients were familiarized with the sensation by holding the probe against the distal palmar surface of the hand, the probe was then applied perpendicular to the distal plantar surface of the big toe of both legs.The voltage slowly increases at the rate of 1 mV/s, and the VPT value can be defined as the voltage level when the patient indicates that he or she first feels the vibration sense.The mean of three readings at each site was taken; the higher vibration unit value indicates poorer performance or greater sensory dysfunction.

Neurological Symptom Score and Neurological Disability Score
We have extended our assessment by inquiring about symptoms related to neuropathy.We asked participants whether they were experiencing sensations such as burning, numbness, tingling, fatigue, cramping, and aching.If patients reported experiencing any of these symptoms, we further inquired about the specific location, whether it was in their feet, calves, or elsewhere.In addition, we investigated whether symptoms worsened during the day, at night, or both and how patients found relief, whether through activities such as walking, standing, or sitting/lying down.We have employed the NSS, which is a widely used system that assesses neurological symptoms including burning, numbness, and tingling, as well as sensations of fatigue, cramps, and aches.If a participant exhibited positive symptoms, we asked detailed questions about the timing, location, and methods of symptom relief.The NSS score ranges from 0 to 9, with scores of 0-2 considered normal, 3-4 categorized as mild, 5-6 as moderate, and 7-9 as severe. 15o evaluate the impact of neuropathy on patients' daily lives, we conducted clinical tests to assess ankle reflex, sensory impairment (including loss of vibration, proprioception, pain, temperature, and touch sensation), and the extent of sensory loss.The results were documented using the NDS VOL.2024 / ART.24   Using biothesiometer, Neuropathy Symptom Score, and Neuropathy Disability Score for the early detection When biothesiometer readings indicate mild to severe peripheral neuropathy, this condition is categorized as "peripheral neuropathy."Conversely, when biothesiometer readings fall within the typical range, they are classified as "no peripheral neuropathy." 8 In addition, when using biothesiometry to diagnose peripheral neuropathy, 14

Statistical analysis
Statistical analyses were performed using version 26.0 of the Statistical Package for the Social Sciences. 18Descriptive statistics were utilized to compute the mean and standard deviation (SD) or median and interquartile range (IQR) for the baseline characteristics of the study participants.The association between categorical data was examined using either chi-square test.The association between continuous data and categorical data was examined using independent Student's t-test or one-way ANOVA test.The level of statistical significance was set at a p-value <0.05.

Ethical approval
We obtained ethical clearance from the Medical Research Ethics Committee (MREC), Ministry of Health Malaysia, under reference NMRR-20-971-54860, and from the Ethics Committee for Research Involving Human Subjects, Universiti Putra Malaysia, with reference number JKEUPM-2020-367.A written consent was obtained from all respondents prior to data collection.

RESULTS
In this study, a total of 1283 participants were enrolled with an average age of 40.6 ± 12.9 years.The majority of the participants were of Chinese system, which can have a maximum score of 10.The NDS is categorized as normal, mild, moderate, or severely disturbed based on scores ranging from 0 to 2, 3 to 5, 6 to 8, and 9 to 10, respectively. 15,16

Operational definition
Peripheral neuropathy is operationally defined based on three distinct criteria, and a positive diagnosis is established if any one of the following conditions is met: Peripheral neuropathy is diagnosed by employing the NSS and NDS questionnaires.In accordance with Young's criteria 15 , a positive diagnosis of peripheral neuropathy is confirmed when the combined score of the NSS and NDS exceeds 10.The sensitivity and specificity for NDS+NSS >10 in detecting early DPN were 71 and 90% 15 .Clinical studies have provided strong validation for the utilization of VPT in the diagnosis of neuropathy, as evidenced by its sensitivity and specificity of 80 and 98%, respectively. 9This is additionally supported by extensive prospective epidemiological studies which demonstrate that a VPT exceeding 25 mV exhibited a sensitivity of 83% and a specificity of 63%. 8atients scoring 10 or below are categorized as having normal results.Peripheral neuropathy is diagnosed based on clinical examination findings, which include the presence of any of the following physical signs in one or both lower limbs: diminished or absent ankle reflex; reduced vibration sensation as determined by a 128-Hz tuning fork; impaired pinprick sensation, indicating a reduced ability to perceive pain; and altered temperature discrimination.The assessments on ankle reflex and sensory impairment were conducted by two trained doctors and validated by experienced researchers who consist of family medicine specialists and neurologists.Peripheral neuropathy diagnosis can also be established through the utilization of the biothesiometer test. 8Specific cutoff values are employed to determine the presence of peripheral neuropathy: A value below 15 V is indicative of the absence of peripheral neuropathy; a range of 15-24.9V suggests mild peripheral neuropathy; and a value of 25 V or more indicates significant peripheral neuropathy.ethnicity (54.1%) and 43.4% had completed tertiary education.A significant proportion of the participants did not consume alcohol (80.6%), were non-smokers (83.5%), and were nonvegetarian (97.6%).Among the participants, the percentage of individuals with hypertension (21.8%) was higher than those with diabetes (12.9%).In addition, a small proportion of participants reported having underlying neurological problems (3.2%) and 7.3% had a family history of neurological problems (Table 1).Age is a significant factor, with increasing neuropathy severity in older participants.Males were more likely to exhibit severe peripheral  A positive clinical examination is determined by the presence of any physical examination findings on either one or both lower limbs, as described below: reduced or absence of ankle reflex or reduced vibration sensation using a 128-Hz tuning fork or reduced pinprick sensation (i.e., reduced ability to feel pain) or reduced temperature discrimination.SD, standard deviation.neuropathy compared with females.In addition, the Indian ethnic group displayed higher severity levels compared with others.
In the case of the NSS, age was strongly associated with symptom severity, with older individuals experiencing more severe symptoms.However, gender and ethnicity did not significantly associate NSS scores.For the NDS, age remained a critical factor, indicating that older individuals had more severe disability.Gender did not show a substantial neuropathy.The PPV was 1.00, meaning that the probability of having peripheral neuropathy given a positive test result was 100%.The NPV was 0.79, indicating that the probability of not having peripheral neuropathy given a negative test result was 79% (Table 3).
The sensitivity and specificity findings of this study apply specifically to the Diabetic Foot Care Model: Vibrometer-VPT model 1.While there may be a degree of variability from model to model, we did not cross-reference the data with other models.Consequently, the results must be interpreted with caution.

DISCUSSION
The study was on the accuracy of the NSS, the NDS, and the biothesiometer against clinical examination findings for the identification of peripheral neuropathy among adults in retail pharmacies in Selangor, Malaysia.Peripheral neuropathy diagnosis based on clinical examination findings was used as the standard test which reflects the real-life situation when compared with NDS, NSS, and the biothesiometer test.
The results of the study showed that age was a significant factor in determining neuropathy severity across all screening tools.Older participants exhibited more severe neuropathy symptoms, disability, and clinical examination abnormalities.Males were more likely to exhibit severe peripheral neuropathy compared with females, and the Indian ethnic group displayed higher severity levels compared with others in the biothesiometry test.However, gender and ethnicity had varying impacts on neuropathy severity depending on the assessment method.The findings of this study are consistent with previous research that has shown age to be a significant factor in determining neuropathy severity. 19The biothesiometry test, in particular, has been shown to be a reliable and sensitive tool for detecting neuropathy severity in older individuals. 20The NSS and NDS tests have also been shown to be useful in assessing neuropathy severity, with age being a critical factor in determining symptom severity and disability. 8owever, the impact of gender and ethnicity on neuropathy severity has been less consistent across different assessment methods. 21,22sociation with NDS scores, while ethnicity played a notable role in determining neuropathy severity.
In clinical examination findings, age was again a significant determinant, with increasing abnormalities in older individuals.Gender did not show a significant association with clinical examination results, but ethnicity, specifically the Indian demographic, exhibited a higher prevalence of abnormalities compared with others.In summary, age consistently influences neuropathy severity across all screening tools, while the impact of gender and ethnicity varies depending on the assessment method.These findings shed light on the intricate relationship between demographic factors and neuropathy assessment (Table 2).Table 3 shows the effectiveness of biothesiometer test, NSS, NDS, and a combination of NSS and NDS in screening for peripheral neuropathy.Regarding the biothesiometer test, 182 participants had a positive test result for peripheral neuropathy based on clinical examination findings, while 109 had a negative result.Among those with a positive biothesiometer result, 53% actually had peripheral neuropathy, while, among those with a negative biothesiometer result, 88% did not have peripheral neuropathy based on clinical examination.The sensitivity of the biothesiometer test was 0.63, meaning that it correctly identified 63% of the participants who had peripheral neuropathy.The specificity was 0.84, indicating that the test correctly identified 84% of the participants who did not have peripheral neuropathy.The PPV was 0.53, meaning that the probability of having peripheral neuropathy given a positive test result was 53%.The NPV was 0.88, indicating that the probability of not having peripheral neuropathy given a negative test result was 88%.
Combining the NSS and NDS with a threshold of greater than 10 improved sensitivity compared with using the individual scores.The combined tool had high specificity and a high PPV, suggesting that it could be a reliable indicator of peripheral neuropathy when both scores are elevated.The sensitivity of this test was very low at 0.11, meaning that it only correctly identified 11% of the participants who had peripheral neuropathy.However, the specificity was very high at 1.00, indicating that the test correctly identified all of the participants who did not have peripheral Using biothesiometer, Neuropathy Symptom Score, and Neuropathy Disability Score for the early detection negatives and missed diagnoses such as subclinical neuropathy. 25Subclinical neuropathy presents in 20% of diabetic patients. 26This highlights the importance of using multiple screening tools and diagnostic tests in the diagnosis of peripheral neuropathy.
On the basis of the symptom profiles and risk factors of patients suspected of having peripheral neuropathy, the results may assist clinicians in selecting appropriate diagnostic procedures.For example, the biothesiometer's suitability for preliminary quantitative sensory evaluation is supported by its comparatively high sensitivity and specificity.The biothesiometer test showed moderate sensitivity (0.64) and specificity (0.84) in diagnosing peripheral neuropathy, making it a reasonable tool for identifying peripheral neuropathy.The test's NPV was particularly high, suggesting its effectiveness in ruling out the condition.These findings are consistent with previous studies that have reported similar sensitivity and specificity values for the biothesiometer test with a cut-off value of ≥20.5 V. 8,17 The sensitivity and specificity increase to 82% and 70% when the cut-off value raises to ≥24.5 V.However, the PPV of the biothesiometer test was low, indicating that a positive test result may not necessarily indicate the presence of peripheral neuropathy.Therefore, further evaluation and diagnostic testing may be required in cases of a positive biothesiometer test result.This may be contributed by the amount of pressure applied to the probe, psychological factors, and choice of limb site. 23For example, biothesiometer is the choice to detect large nerve fiber-related 21 peripheral neuropathy in the lower extremity. 24he combination of the NSS and NDS, with a score greater than 10 indicating a positive test result for peripheral neuropathy, showed high specificity but low sensitivity.While the high specificity indicates that this test is useful in ruling out peripheral neuropathy, the low sensitivity may result in false the following threshold values for vibration perception and corresponding neuropathy categories apply based on age: for individuals over the age of 50 years: 1-15 V: Normal; 16-20 V: Mild; 21-25 V: Moderate; 26-50 V: Severe.Whereas for the individuals aged 50 years and below: 1-10 V: Normal; 11-15 V: Mild; 16-20 V: Moderate; 21-50 V: Severe.Neurological disorders are defined as Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy.

Table 3 . Sensitivity, specificity, positive predictive value, and negative predictive values of screening tools based on biothesiometer, neuropathy symptom score, and neuropathy disability score (n = 1283).
Have peripheral neuropathy based on clinical examination findings which include the presence of any of the following physical signs in one or both lower limbs: diminished or absent ankle reflex or reduced vibration sensation as determined by a 128-Hz tuning fork or impaired pinprick sensation, indicating a reduced ability to perceive pain or altered temperature discrimination.NSS, Neurological Symptom Score; NDS, Neurological Disability Score. *

Table 4 . Summary of the sensitivity, specificity, and problem encountered by different diagnostic tools in detecting peripheral neuropathy.
NSS, Neurological Symptom Score; NDS, Neurological Disability Score; MNSI, The Michigan Neuropathy Screening Instrument.